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Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxide

Nature Chemistry volume 10, pages 787–794 (2018)Cite this article

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Abstract

Controlled activation is a critical component in prodrug development. Here we report a concentration-sensitive platform approach for bioorthogonal prodrug activation by taking advantage of reaction kinetics. Using two ‘click and release’ systems, we demonstrate enrichment and prodrug activation specifically in mitochondria to demonstrate the principle of the approach. In both cases, the payload (doxorubicin or carbon monoxide) was released inside the mitochondrial matrix following the enrichment-initiated click reaction. Furthermore, mitochondria-targeted delivery yielded substantial augmentation of functional biological and therapeutic effects in vitro and in vivo when compared to controls, which did not result in enrichment. This method is thus a platform for targeted drug delivery that is amenable to conjugation with a variety of molecules and is not limited to cell-surface delivery. Taken together, these two 'click and release' pairs clearly demonstrate the concept of enrichment-triggered drug release and the critical feasibility of treating clinically relevant diseases such as acute liver injury and cancer.

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Fig. 1: Schematic of the concept of enrichment-triggered prodrug activation.
Fig. 2: Cytotoxicity of click and release pairs in HeLa cells.
Fig. 3: Fluorescence imaging studies of the click reaction between 21 and 22 in RAW264.7 cells.
Fig. 4: CO prodrugs protect against acute liver failure.

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Acknowledgements

The authors thank Z. Liu at the Center for Molecular and Translational Medicine at Georgia State University for taking confocal images. The authors also acknowledge GSU Molecular Basis of Disease (Z.P. and M.R.C.), Brains & Behaviors (B.Y.) and University 2CI (L.K.C.d.l.C.) fellowships for their support, and the Department of Defense Peer Reviewed Medical Research Program (W81XWH-16-0464 and NIH R44 DK111260-02 to L.E.O.).

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Author notes

  1. These authors contributed equally: Yueqin Zheng, Xingyue Ji.

Authors and Affiliations

  1. Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA

    Yueqin Zheng, Xingyue Ji, Bingchen Yu, Kaili Ji, Mengyuan Zhu, Manjusha Roy Choudhury, Ladie Kimberly C. De La Cruz, Vayou Chittavong, Zhixiang Pan, Zhengnan Yuan & Binghe Wang

  2. Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA

    Yueqin Zheng, Xingyue Ji, Bingchen Yu, Kaili Ji, Mengyuan Zhu, Manjusha Roy Choudhury, Ladie Kimberly C. De La Cruz, Vayou Chittavong, Zhixiang Pan, Zhengnan Yuan & Binghe Wang

  3. Harvard Medical School, Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA

    David Gallo, Eva Csizmadia & Leo E. Otterbein

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Contributions

B.W. conceived the initial idea, and supervised the study and the overall manuscript preparation and revision process. B.W. also revised the manuscript. Y.Z. and X.J. designed and performed the experiments, and drafted the manuscript. B.Y. and K.J. conducted the in vitro biology studies. D.G. and E.C. performed the in vivo studies. M.Z carried out the computational work. M.R.C., L.K.C.d.l.D., V.C., Z.Y., and Z.P. conducted studies of the reaction kinetics and some of the synthesis. L.E.O supervised and/or performed the in vivo studies, analysed and interpreted the data, and revised the manuscript. All authors reviewed, edited and approved the manuscript.

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Correspondence to Leo E. Otterbein or Binghe Wang.

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L.E.O. is a scientific consultant for Hillhurst Biopharmaceuticals. All other authors declare no competing interests.

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Zheng, Y., Ji, X., Yu, B. et al. Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxide. Nature Chem 10, 787–794 (2018). https://doi.org/10.1038/s41557-018-0055-2

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